Effect of delta-9-tetrahydrocannabinol on behavioral despair and on pre- and postsynaptic
serotonergic transmission.

Abstract

Preclinical and clinical studies suggest that direct and indirect cannabinoid agonists,
including enhancers of endocannabinoids, engender stress-relieving, anxiolytic and
antidepressant effects, mediated by central CB(1) receptors (CB(1)Rs). The effect
of the main pharmacologically active principle in cannabis, (-)-trans-Δ(9)-tetrahydrocannabinol
(delta-9-THC), on depressive behavior and on the serotonin (5-HT) system, which is
implicated in the mechanism of action of antidepressants, has not been extensively
clarified. Here, we showed that repeated (5 days), but not single (acute) intraperitoneal
(ip) treatment with delta-9-THC (1mg/kg) exerts antidepressant-like properties in
the rat forced swim test (FST). This effect was CB(1)R-dependent because it was blocked
by the CB(1)R antagonist rimonabant (1mg/kg, ip). Using in vivo electrophysiology,
we demonstrated that delta-9-THC modulated dorsal raphe (DR) 5-HT neuronal activity
through a CB(1)R-dependent mechanism. Acute intravenous delta-9-THC administration
(0.1-1.5mg/kg) elicited a complex response profile, producing excitatory, inhibitory
and inert responses of 5-HT neurons. Only excitatory responses were blocked by rimonabant.
Finally, repeated but not single delta-9-THC administration (1mg/kg, ip) enhanced
tonic 5-HT(1A) receptor activity in the hippocampus, a postsynaptic event commonly
elicited by standard antidepressants. These results suggest that delta-9-THC, like
other CB(1)R agonists and endocannabinoid enhancers, may possess antidepressant properties
at low doses, and could modulate 5-HT transmission in the DR and hippocampus as standard
antidepressants such as selective serotonin reuptake inhibitors.